rs767341738

Variant names:

• chr10-18539273-GT-G
• rs767341738
• NM_201596.3:c.1534delT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_201596.3(CACNB2):​c.1534delT​(p.Ser512LeufsTer57) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CACNB2 NM_201596.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -2.21

Genes affected

CACNB2 (HGNC:1402): (calcium voltage-gated channel auxiliary subunit beta 2) This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The gene product was originally identified as an antigen target in Lambert-Eaton myasthenic syndrome, an autoimmune disorder. Mutations in this gene are associated with Brugada syndrome. Alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Feb 2013]

ENSG00000240291 (HGNC:58168):

LOC124902386 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNB2	NM_201596.3	c.1534delT	p.Ser512LeufsTer57	frameshift_variant	Exon 14 of 14	ENST00000324631.13	NP_963890.2
CACNB2	NM_201590.3	c.1372delT	p.Ser458LeufsTer57	frameshift_variant	Exon 13 of 13	ENST00000377329.10	NP_963884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNB2	ENST00000324631.13	c.1534delT	p.Ser512LeufsTer57	frameshift_variant	Exon 14 of 14	1	NM_201596.3	ENSP00000320025.8
CACNB2	ENST00000377329.10	c.1372delT	p.Ser458LeufsTer57	frameshift_variant	Exon 13 of 13	1	NM_201590.3	ENSP00000366546.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251384 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 4 Uncertain:2

Nov 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser458Leufs*57) in the CACNB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 149 amino acid(s) of the CACNB2 protein. This variant is present in population databases (rs767341738, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CACNB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 402478). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Mar 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Ser512fs in CACNB2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 512 and leads to a premature termination codon 57 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. LoF not a known disease mechanism. In summary, the clinical significance of the p.Ser512fs variant is uncertain. -

Cardiovascular phenotype Uncertain:1

Jul 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1372delT variant, located in coding exon 13 of the CACNB2 gene, results from a deletion of one nucleotide at nucleotide position 1372, causing a translational frameshift with a predicted alternate stop codon (p.S458Lfs*57). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of CACNB2 has not been clearly established as a mechanism of disease. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767341738; hg19: chr10-18828202;